A new clue to a serious neurodegenerative disease

• The new findings provide insight into the fundamental biology of frontotemporal dementia, a devastating neurodegenerative disease caused by mutations in specific genes

• The researchers found that an inherited form of frontotemporal dementia is associated with abnormal lipid accumulation in the brain, which is caused by cellular metabolic disorders

• The study revealed a fundamental aspect of the mechanisms that lead to frontotemporal dementia, and the findings may help design targeted treatments

Dementia includes a range of neurodegenerative diseases that can lead to memory loss and cognitive deficits, affecting around 55 million people
worldwide.
However, despite its popularity, there are few effective treatments, in part because scientists still don't understand exactly how dementia occurs
at the cellular and molecular level.

Now, a team led by scientists at Harvard Medical School and Harvard t.
h.
Chan School of Public Health has made progress
in uncovering the underlying mechanisms of dementia that occurs early in life.

In a study published Oct.
7 in Nature Communications, researchers found that an inherited form of frontotemporal dementia (FTD) is associated with the accumulation of specific lipids in the brain that interferes with cellular metabolism
due to protein deficiencies.

The experimental results based on human brain cells and animal models provide new insights for the study of temporal lobe neuralgia, which can provide reference
for the design of new therapies.
In addition, the researchers say, the findings highlight a mechanism of metabolic disorders that may be linked to
other forms of neurodegeneration.

A black box

There are several different types of dementia, each with complex genes that involve a variety of mutations
.
Temporal lobe dementia, characterized by a decrease in frontal and temporal lobe cells of the brain, accounts for 5% ~ 10%
of dementia cases.
Usually diagnosed in patients between the ages of 45 and 65, this form of the gene tends to cluster
in families.
About 15 percent of the time, temporal lobe fatigue is associated with a specific mutation in the GRN gene that causes brain cells to stop making a protein
called progranulin.

Previous studies have linked
process proteins to lysosomes in cells responsible for cellular cleanup and other metabolic activities.
However, "the function of this protein, including its role in lysosomes, remains a kind of black box," said co-senior author Wade Harper, the Bert and Natalie Vallee Professor
of Molecular Pathology in the Department of Cell Biology at the HMS Blavatnik Institute.

Harper collaborated on the study with co-senior authors Tobias Walter and Robert Farese Jr.
, who were professors of cell biology at HMS and professor of molecular metabolism at Harvard Chan School when they conducted the study, as well as lead author Sebastian Boland, former investigators in Farese & Walther's lab, and Sharan Swarup.
Former researcher
in Harper's lab.

The researchers initially found that human cell lines and mouse brains lacking programmed proteins, as well as brain cells from patients with temporal lobe neurosis, had accumulation of ganglioside, a lipid
that is ubiquitous in the nervous system.

Next, the team used recently developed techniques for purifying lysosomes to analyze the type and number
of proteins and lipids inside lysosomes.
With this technique, the scientists found that lysosomes in these cells and tissues from the brains of FTD patients had reduced levels of progranulin, as well as lower than normal levels of a lipid called BMP, which is necessary to break down gangliosides, a common lipid
in the central nervous system.
However, when the researchers added BMP to the cells, they observed that the cells accumulated much
lower levels of gangliosides.

Together, the findings suggest that programmed proteins in lysosomes help maintain levels of BMP to prevent ganglioside accumulation in brain cells, which can lead to FTD
.

"We have found a role for programmed proteins in supporting the proper degradation of gangliosides," Farese said, while also suggesting that it may correct this problem
.

Walther added: "Treatments that give patients procedural protein sources are already being studied, and our results are consistent with
the potential therapeutic effects of this approach.
In addition, it is possible to develop treatments that focus on replacing BMP rather than process proteins, thus targeting different parts of
the mechanism.
”

The researchers also think that similar lysosome-based mechanisms may be associated with neurodegenerative diseases other than FTD — an idea they note is rapidly gaining acceptance
in the field.

"Lysosomes may be a key feature of a variety of neurodegenerative diseases, but these diseases may all be linked to lysosomes in different ways," Harper said
.
For example, scientists already know that a protein associated with the inherited form of Parkinson's controls certain aspects of
lysosomal function.
Farese added that more research is needed to understand exactly how various lipids and proteins interact with lysosomes in the context of
different neurodegenerative diseases.

Now, researchers are studying several genes involved in lysosomal function, including those associated with lysosomal storage diseases, to find links
between them.
The remaining central question is how the process protein raises BMP levels in the brain
.
More research is needed to further elucidate the mechanistic steps the team found and explain how lipid accumulation translates into cognitive decline
.

"This study demonstrates the power of collaboration and following science," Walther said
.
"By using the right tools and asking the right detailed questions, sometimes you can uncover unexpected things
.
"

Deficiency of the frontotemporal dementia gene GRN results in gangliosidosis